Method of enhancing diabetes resolution

ABSTRACT

Disclosed are compositions and methods for increasing diabetes resolution in a diabetic patient having undergone gastric restrictive surgery, entailing use of active agent that produces an incretin-like effect in the patient.

CROSS-REFERENCE RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 12/744,099, filed on Aug. 24, 2010, which application is anational phase entry under 35 U.S.C. §371 of International ApplicationNo. PCT/US2008/013122, filed Nov. 21, 2008, published in English, whichclaims priority from U.S. Provisional Patent Application No. 61/004,086,filed Nov. 23, 2007, all of which are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted via EFS-Web and is hereby incorporated by reference in itsentirety. Said ASCII copy, created on Feb. 17, 2014, is namedMROTH3.3-001_SL.txt, and is 23,735 bytes in size.

BACKGROUND OF THE INVENTION

Obesity is has become a health concern of global proportion. TheNational Center for Health Statistics (NCHS) estimates that over 120million Americans are overweight, including about 56% of the adultpopulation. Of these, about 52 million are considered obese, as measuredby a body mass index (BMI) of 30% or greater. In Europe, an estimated 77million people are obese, as measured by the same standard. This problemis not limited to western nations, as many developing countries arereported to have obesity rates over 75% of the adult population.

Type II Diabetes is a significant factor in the obese. Type II diabetesis characterized by a gradual loss of insulin secretion and aprogressive reduction in β-cell mass. Insulin resistance increases thedemand for insulin. As the β-cell mass declines, the pancreas is unableto sustain the high insulin levels required to maintain normoglycemia.

Weight loss, diet alteration and exercise can improve glycemic control.Beyond these measures, medical therapy of diabetes is intended tocontrol blood sugar within acceptable limits. Patients with diabeteshave a wide a number of therapeutic approaches. Medications such assulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidaseinhibitors are available orally. Insulin can be injected or inhaled.Recently a new class of drugs, labeled incretin-mimetics, aimed atenhancing the incretin effect, has been introduced. Many of these drugs,e.g., exenatide, require injection. As effective as they are, however,patients with diabetes can be expected to remain on diabetic medicationsfor their entire lives.

Surgical options exist for obese diabetics, including relativelyinvasive surgeries such as gastric bypass surgery and duodenal switchsurgery, and less invasive surgeries referred to as gastric restrictionsurgeries. In both gastric bypass and duodenal switch surgery, thecapacity of the stomach is significantly reduced and a portion of thesmall intestine is rerouted. However, the degree of malabsorption isgreater in duodenal switch surgery than gastric bypass surgery. Gastricrestriction surgeries differ from bypass techniques in that the stomachcapacity is reduced but the intestine is left substantially intact.

Diabetes resolution occurs in 48-95% of post-surgical patients,depending on the specific surgery. Thus surgery offers the potential ofachieving complete resolution of type II diabetes. This enables patientsto stop diabetic medications and glucose self-monitoring entirely.

Gastric bypass procedures (RYGB) incur a great deal of morbidity andcreate a malabsorptive state in the patient by passing a large portionof the intestines. Diabetes resolution (dR) has been reported to occurin 84% of patients after gastric bypass surgery. Cummings, et al.,Surgery for Obesity and Related Diseases 3:109-15 (2007).

Gastrointestinal sleeves have been implanted to line the stomach and/ora portion of the small intestines to reduce the absorptive capabilitiesof the small intestine and/or to reduce the volume in the stomach, byreducing the available volume to the tubular structure of the graftrunning there through. Although weight loss may be effective while thesetypes of devices are properly functioning, there are complications withanchoring the device within the stomach/GI tract, as the stomach and GItract function to break down things that enter into them and tomove/transport them through. Accordingly, the integrity of the anchoringof the device, as well as the device itself may be compromised over timeby the acids and actions of the stomach and GI tract.

A sleeve gastrectomy is an operation in which the left side of thestomach is surgically removed. This results in a much reduced stomachwhich is substantially tubular and may take on the shape of a banana.This procedure is associated with a high degree of morbidity, as a largeportion of the stomach is surgically removed. Additionally, there arerisks of complications such as dehiscence of the staple line where thestaples are installed to close the surgical incisions where the portionof the stomach was removed. Further, the procedure is not reversible.

In the laparoscopic duodenal switch (also referred to as biliopancreaticdiversion or BPD), the size of the stomach is reduced in similar mannerto that performed in a sleeve gastrectomy. Additionally, approximatelyhalf of the small intestine is bypassed and the stomach is reconnectedto the shortened small intestine. This procedure suffers from the samecomplications as the sleeve gastrectomy, and even greater morbidity isassociated with this procedure due to the additional intestinal bypassthat needs to be performed. Still further, complications associated withmalabsorption may also present themselves. Diabetes resolution has beenreported to occur in 95% of patients after duodenal switch surgery(BPD). This diabetes resolution may occur within days after RYGB andBPD, often even before significant weight loss has occurred.

Gastric reduction or restrictive techniques have also been attempted.Unlike bypass procedures, these techniques do not involve reduction ofintestinal volume. Such reduction or restrictive techniques includeinserting instruments trans-orally and reducing the volume of thestomach by stapling portions of it together. The LAPBAND™ is a bandthat, when placed, encircles the fundus-cardia junction and isinflatable to constrict the same. It does not reduce the volume of thestomach, but rather restricts passage of food into the stomach, thetheory being that the patient will feel satiety with a much less volumeof food than previously. Diabetes resolution has been reported to occurin only 48% of patients after gastric restriction surgery, such asadjustable gastric binding (i.e., the LAPBAND™). Cummings, et al.,Surgery for Obesity and Related Diseases 3:109-15 (2007).

SUMMARY OF THE INVENTION

An aspect of the present invention is directed to a method forincreasing diabetes resolution in a type II diabetic patient havingundergone gastric restrictive surgery comprising administering to thepatient an agent that produces or causes an incretin-like effect in thepatient, in an amount effective to achieve diabetes resolution. In someembodiments, the agent is an incretin hormone such as glucagon-likepeptide 1 (GLP-1), gastric inhibitory protein (GIP), or an analog orderivative thereof of GLP-1 or GIP. In some other embodiments, the agentis not an incretin hormone, per se, but acts to increase endogenousincretin hormone activity level, such as by inhibiting degradation ofendogenous incretin hormones. In some embodiments, the agent is a DPP IVinhibitor.

The present invention increases diabetic resolution in type II diabeticpatients after gastric restriction surgery, thus allowing them todiscontinue treatment and medication for diabetes indefinitely or evenpermanently, and may also improve weight loss outcomes.

DETAILED DESCRIPTION

As used herein, diabetes resolution generally refers to the restorationof normal glucose metabolism, the presence of which can be determined bystandard techniques in the art as described and/or referenced herein.The term “administer” (or administered or administering) as used hereinincludes administration by the patient him/herself.

As used herein, gastric restriction surgery refers to surgeries in whichthe stomach is altered in a manner that restricts the normal passage offood, leading to a reduction in food intake. This can be accomplished bya reduction in the overall stomach size, a reduction in the gastriccapacity or a change in the stomach configuration. Gastric restrictionsurgery differs from RYGB and BPD because it does not involve a bypass(and thus reduction) of the small intestine. As a result, gastricrestriction surgery does not increase the output of gastrointestinalhormones from the K and L cells. Exemplary illustrations of gastricrestriction surgeries include LAPBAND™ surgery (adjustable gastricbinding) and vertical banded gastroplasty. Other illustrations ofgastric restriction surgeries include gastric stapling, gastricpartitioning and gastric plication.

Diabetes Mellitus exists in two forms, type I and type II. Type Idiabetics have a severe deficiency of insulin production from theβ-cells of the pancreatic islets. Their endogenous insulin production isvery, very low, and thus inadequate to regulate blood glucose levels.They require injections of insulin to keep their blood glucosenormalized and to prevent keto-acidosis. In contrast, type II diabetesis characterized by insulin resistance, which means that additionalamounts of insulin must be produced to achieve the same decrease inblood glucose. Insulin resistance generally refers to a condition inwhich normal amounts of insulin are inadequate to produce a normalinsulin response from fat, muscle and liver cells. Insulin resistance infat cells results in hydrolysis of stored triglycerides, which elevatesfree fatty acids in the blood plasma. Insulin resistance in musclereduces glucose uptake, whereas insulin resistance in liver reducesglucose storage, with both effects serving to elevate blood glucose.

Over time, the disease progress to a point where pancreatic cellproduction of insulin fails to keep up with the body's demand, resultingin an increasingly wide gap between the body's requirements for insulinand its own insulin production. Insulin resistance can be caused by manydifferent kinds of factors, including obesity, medication and geneticfactors. Thus, type II diabetics make insulin sufficient to preventketoacidosis but not enough to meet the heightened requirements of theirinsulin-resistant state. Accordingly, treatment of type II diabetes isintended to control three factors, namely glucose delivery, insulinresistance and insulin production.

Without intending to be found by theory, Applicant hypothesizes that thewide difference in diabetes resolution observed between gastricrestriction surgery, which has been reported to be about 48%, and theintestinal bypass or diversion procedures, which has been reported to beabout 84%, is due to intestinal factors, and that increasedgastrointestinal hormone secretion and particularly incretin hormonesecretion, creates a metabolic influence in favor of diabetes resolutionafter RYGB and BPD. The gastric restriction surgery reduces food intakeand therefore lowers glucose delivery. The weight loss that typicallyresults from gastric restriction surgery reduces insulin resistance.Therefore, the present inventor hypothesizes that the differenceobserved in diabetes resolution between gastric restriction surgery andRYGB is most likely due to the lack of increased intestinal hormonesecretion after gastric restriction surgery. In other words, both typesof surgery achieve control of glucose intake because they cause thepatient to ingest less food, albeit in very different ways. However, theincreased hormone secretion observed after RGYB corrects the imbalancebetween insulin resistance and insulin production, and achieves arestoration of normal glucose metabolism and blood levels.

The present invention, therefore, addresses each of these three factors.The invention makes further use of agents with incretin-like activity orwhich produce or cause an incretin-like effect, which for purposes ofthe present invention, includes decreased glucose delivery (e.g.,appetite reduction, increased satiety and/or slowed gastric emptying),reduced insulin resistance and increased insulin production. Basically,the patient may experience a restoration of normal incretin response toglucose challenge or a supra-normal incretin response to glucosechallenge. The combination of this therapeutic intervention not onlyenhances the effects of gastric restriction surgery by lowering glucosedelivery (resulting in lower, e.g., normal, levels of fasting blood orserum glucose) and reducing insulin resistance, but these agents also gofurther by increasing insulin production. Thus, the combination ofgastric restriction surgery and agents with incretin-like activityincrease diabetes resolution beyond the 48% reported in the literatureas achievable with gastric restriction surgery alone. In someembodiments, the increased diabetes resolution may be as high as 80% orbetter.

Diabetic patients for whom gastric restriction surgery is recommendedtend to be obese. Unless stated otherwise in connection with anyspecific embodiments disclosed herein, treatment with the agent(s) ofthe present invention may begin any time after gastric restrictionsurgery, but usually about 3 months thereafter. By this time, it is moreprobable that diabetes resolution will have occurred without therapeuticintervention. Timing of the administration is not critical, but isdesirably within 1 hour of a meal. Although the time course of thehormone therapy may vary for each patient, the duration of treatmentgenerally ranges from about 1 to about 24 months.

When diabetes resolution occurs after gastric restriction surgery (e.g.,LAPBAND™), it usually takes several months and often requires weightloss. Thus, there is a fundamental difference in diabetes resolution ingastric restriction surgery compared to more invasive forms of bariatricsurgery to treat obesity. Active agents suitable for use in the presentinvention include incretin hormones, per se, (including both natural andsynthetic versions thereof), analogs, derivatives and mimetics of suchhormones, and agents that increase endogenous activity levels ofincretin hormones.

Incretin hormones suitable for use in the present methods are recognizedto play an important role in food intake, weight loss and glycericresponse. These include GLP-1 (glucagon like peptide-1) and GIP (gastricinhibitory peptide, also known as glucose-dependent insulinotropicpolypeptide). Together with autonomic nerves they play a vitalsupporting role to the pancreatic islets in the control of blood glucosehomeostasis and nutrient metabolism.

Human GLP-1 is a 37-amino acid peptide (SEQ ID NO:1) originating frompreproglucagon, which is synthesized for example, in the L-cells in thedistal ileum, in the pancreas and in the brain, and then furtherprocessed into shorter peptide(s), e.g., GLP-1 (7-36)amide (SEQ IDNO:2). GLP-1 is normally secreted in response to food intake inparticular carbohydrates and lipids stimulate GLP-1 secretion. GLP-1 hasbeen identified as a very potent and efficacious stimulator for insulinrelease. GLP-1 has been reported to lower plasma glucagonconcentrations, slow gastric emptying, stimulate insulin biosynthesis,enhance insulin sensitivity, and enhance the ability of the B-cells tosense and respond to glucose in subjects with impaired glucosetolerance. The insulinotropic effect of GLP-1 in humans has beenreported to increase the rate of glucose metabolism partly due toincreased insulin levels and partly due to enhanced insulin sensitivity.Other studies have shown that infusions of slightly supra-physiologicalamounts of GLP-1 significantly enhance satiety and reduce food intake innormal subjects, and that the effect on food intake and satiety ispreserved in obese subjects.

As used herein, a “GLP-1 analog” refers to a molecule having amodification including one or more amino acid substitutions, deletions(e.g., fragments), inversions, or additions when compared with GLP-1. Auseful GLP-1 analog is GLP-1(7-37), which is represented by thesequence:NH₂-His⁷-Ala-Glu-Gly¹⁰-Thr-Phe-Thr-Ser-Asp¹⁵-Val-Ser-Ser-Tyr-Leu²⁰-Glu-Gly-Gln-Ala-Ala²⁵-Lys-Glu-Phe-Ile-Ala³⁰-Trp-Leu-Val-Lys-Gly³⁵-Arg-Gly³⁷-COOH(SEQ ID NO:3). Other GLP-1 analogs known in the art and that may beuseful in the practice of the present invention include, for example,GLP-1(7-34) (SEQ ID NO:4) and GLP-1(7-35) (SEQ ID NO:5), GLP-1(7-36)(SEQ ID NO:6), Val⁸-GLP-1(7-37) (SEQ ID NO:7), Gln⁹-GLP-1(7-37) (SEQ IDNO:8), D-Gln⁹-GLP-1(7-37) (SEQ ID NO: 57), Thr¹⁶-Lys¹⁸-GLP-1(7-37) (SEQID NO:9), and Lys¹⁸-GLP-1(7-37) (SEQ ID NO:10), among which includebiologically processed versions of full-length GLP-1.

Yet other suitable GLP-1 analogs include exendins (see, e.g., U.S.Patent Application Publication 20060189520), which are peptides that arefound in the venom of the Gila-monster, a lizard found in Arizona, andthe Mexican Beaded Lizard. Exendin-3 is present in the venom ofHeloderma horridum, and exendin-4 is present in the venom of Helodermasuspectum. The exendins have some sequence similarity to several membersof the glucagon-like peptide family, with the highest homology, 53%,being to GLP-1[7-36]NH₂ (SEQ ID NO:11) (Goke, et al., J. Biol. Chem.268:19650-55 (1993)). Like GLP-1 (SEQ ID NO:1), exendins have also beenreported to inhibit gastric emptying.

Exendins suitable for use in the present invention include exendin-3(which is represented by the amino acid sequence: His Ser Asp Gly ThrPhe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe IleGlu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser] (SEQ IDNO:12), and exendin-4 (which is represented by the amino acid sequence:His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu AlaVal Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala ProPro Pro Ser] (SEQ ID NO:13), and other compounds, called exendinagonists, which effectively bind to the receptor at which exendin exertsits action on reducing food intake. Representative exendin agonistsinclude exendin-4 (1-30) (SEQ ID NO:14), exendin-4 (1-30) amide (SEQ IDNO:15), exendin-4 (1-28) amide (SEQ ID NO:16), ¹⁴Leu, ²⁵Phe exendin-4amide (SEQ ID NO:17), ¹⁴Leu, ²⁵Phe exendin-4 (1-28) amide (SEQ IDNO:18), and ¹⁴Leu, ²²Ala, ²⁵Phe exendin-4 (1-28) amide (SEQ ID NO:19).Exendins and exendin agonists that may be useful in the presentinvention are disclosed in U.S. Patent Application Publication Nos.2003/0087821, 2005/0101537 and 2005/0043238.

Exendin compositions useful in the invention may conveniently beprovided in the form of formulations suitable for parenteral (includingintravenous, intramuscular and subcutaneous) or nasal or oraladministration.

As used herein, a “GLP-1 derivative” refers to a molecule having theamino acid sequence of GLP-1 or of a GLP-1 analog, but additionallyhaving at least one chemical modification of one or more of its aminoacid side groups, a-carbon atoms, terminal amino group, (e.g., GLP-1(7-36)amide (SEQ ID NO:2)) or terminal carboxylic acid group. A chemicalmodification includes adding chemical moieties, creating new bonds, andremoving chemical moieties. Modifications at amino acid side groupsinclude acylation of lysine

-amino groups, N-alkylation of arginine, histidine, or lysine,alkylation of glutamic or aspartic carboxylic acid groups, anddeamidation of glutamine or asparagine. Modifications of the terminalamino include the des-amino, N-lower alkyl, N-di-lower alkyl, and N-acylmodifications. Modifications of the terminal carboxy group include theamide, lower alkyl amide, dialkyl amide, and lower alkyl estermodifications. A lower alkyl is a C₁-C₄ alkyl. Furthermore, one or moreside groups, or terminal groups, may be protected by protective groupsknown to the ordinarily-skilled protein chemist. The α-carbon of anamino acid may be mono-methylated or di-methylated. See, e.g., U.S.Patent Application Publication 2004/0018975, and U.S. Pat. Nos.5,118,666 and 5,545,618. Among the GLP-1 analogs and derivatives taughtin U.S. Pat. No. 5,545,618 include those which have amino acidsubstitutions as positions 7-10 and/or are truncated at the C-terminusand/or contain various other amino acid substitutions in the basicpeptide. Analogs and derivatives having D-amino acid substitutions inthe 7 and 8 positions and/or N-alkylated or N-acylated amino acids inthe position are disclosed therein as being particularly resistant todegradation in vivo. Liraglutide (Arg³⁴, Lys²⁶(N^(ε)-(γ-Glu(N^(α)-hexadecanoyl)))-GLP-1(7-37)) (SEQ ID NO:20) is yetanother GLP-1 derivative that may be useful in the present invention.Also known as NN2211, liraglutide is a long acting GLP-1 derivative thatis obtained by acylation of the GLP-1 molecule, which upon entering thebloodstream, is extensively bound to albumin which protects it fromdegradation by DPP-IV and reduces renal clearance. See, Elbrond, et al.,Diabetes Care 25(8):1398-404 (2002); and Madsbad, et al., Diabetes Care27:1335-42 (2004)(and various references cited therein, includingKnudsen, et al., Drugs of the Future 26:677-85 (2001)). As disclosed inMadsband, liraglutide may be administered via i.v. injection,once-a-day, for about 3 months, or even longer at fixed dosages of from0.045-0.75 mg, or higher. It is available commercially from NovoNordisk, Denmark.

GIP is released from intestinal endocrine K-cells into the bloodstreamfollowing ingestion of carbohydrate, protein and particularly fat. GIP'smajor physiological role is now generally believed to be that of anincretin hormone that targets pancreatic islets, and like GLP-1,enhances insulin secretion. (Creutzfeldt, W., Exp. Clin. Endocrinol.Diabetes 109:S288-S303 (2001)). GIP also helps reduce postprandialhyperglycemia. Id. GIP acts through binding to specific G-proteincoupled GIP receptors located on pancreatic beta-cells (Wheeler, et al.,Endocrinology 136:4629-39 (1995)).

Naturally occurring GIP (also referred to as native GIP) is a 42-aminoacid peptide hormone, having the (human) sequence Tyr Ala Glu Gly ThrPhe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys Ile His Gln Gln Asp Phe ValAsn Trp Leu Leu Ala Gln Lys Gly Lys Lys Asn Asp Trp Lys His Asn Ile ThrGln (SEQ ID NO:21). GIP antagonists that are relatively resistant todegradation by DPP IV are also useful in the present invention. Suchantagonists, also referred to as peptide analogues of GIP(1-42), includeGIP(1-12) (SEQ ID NO:22), GIP(1-13) (SEQ ID NO:23), GIP(1-14) (SEQ IDNO:24), GIP(1-15) (SEQ ID NO:25), GIP(1-16) (SEQ ID NO:26), GIP(1-17)(SEQ ID NO:27), GIP(1-18) (SEQ ID NO:28), GIP(1-19) (SEQ ID NO:29),GIP(1-20) (SEQ ID NO:30), GIP(1-21) (SEQ ID NO:31), GIP(1-22) (SEQ IDNO:32), GIP(1-23) (SEQ ID NO:33), GIP(1-24) (SEQ ID NO:34), GIP(1-25)(SEQ ID NO:35), GIP(1-26) (SEQ ID NO:36), GIP(1-27) (SEQ ID NO:37),GIP(1-28) (SEQ ID NO:38), GIP(1-29) (SEQ ID NO:39), GIP(1-30) (SEQ IDNO:40), GIP(1-31) (SEQ ID NO:41), GIP(1-32) (SEQ ID NO:42), GIP(1-33)(SEQ ID NO:43), GIP(1-34) (SEQ ID NO:44), GIP(1-35) (SEQ ID NO:45),GIP(1-36) (SEQ ID NO:46), GIP(1-37) (SEQ ID NO:47), GIP(1-38) (SEQ IDNO:48), GIP(1-39) (SEQ ID NO:49), GIP(1-40) (SEQ ID NO:50), GIP(1-41)(SEQ ID NO:51) and GIP(1-42) (SEQ ID NO:21), where the base peptidepossesses one or more of the following modifications: (1) an amino acidsubstitution at Glu³, e.g., proline, hydroxyproline, lysine, tyrosine,phenylalanine or tryptophan; (2) a modification by fatty acid additione.g., a C-8, C-10, C-12, C-14, C-16, C-18 or a C-20 palmitate (PAL)group to an epsilon amino group of at least one lysine residue e.g.,Lys¹⁶ or Lys³⁷, which have been reported to circumvent the problem ofrenal filtration; and (3) a modification by N-terminal acetylation. See,e.g., U.S. Patent Application Publication 2007/0167370. Althoughliterature categorizes all three categories as GIP-1 antagonists oranalogs, consistent with usage of terminology in the present invention,the modified GIP-1 proteins in the first category are referred to asGIP-1 analogs, and the modified GIP proteins in the latter twocategories are referred to as GIP-1 derivatives. Thus, specificrepresentative GIP analogs and derivatives include N-AcGIP (1-42) (SEQID NO:52), GIP(1-42) (Lys³⁷PAL) (SEQ ID NO:53), N-AcGIP(1-42)(Lys¹⁶PAL)(SEQ ID NO:54) and N-AcGIP(1-42)(Lys³⁷PAL) (SEQ ID NO:55). Furtheranalogs are disclosed in U.S. Patent Application Publication Nos.20020151495, 20030232761, and 2007/0167363 (e.g., GIP (7-30) (SEQ IDNO:56)).

Administration of GIP or its analogs or derivatives of the presentinvention used in the pharmaceutical composition or to practice themethod of the present invention can be carried out in a variety ofconventional ways, such as by oral ingestion, inhalation, topicalapplication or cutaneous, subcutaneous, intraperitoneal, parenteral orintravenous injection.

Dipeptidyl peptidase IV (DPP-IV) inhibitors refer to compounds thatinhibit activity of DPP-IV, a membrane-associated amino peptidase of 766amino acids that acts preferentially on substrates with anamino-terminal proline or alanine at position 2, such as GLP-1, GLP-2,and GIP. Inhibitors of DPP-IV have been shown to increase circulatinglevels of GLP-1 and GIP; thus, they may show an enhanced effect ondiabetes resolution for purposes of the present invention. SuitableDPP-IV inhibitors include sitagliptin((R)-3-Amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]-pyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one,described in WO 03/004498, and commercially available from Merck & Co.),vildagliptin (pyrrolidine,1-[(3-hydroxy-1-adamantyl)amino]acetyl-2cyano-, (S), or(S)-1-2-((5S,7S)-3-Hydroxy-adamantan-1-ylamino)-acetyl]-pyrrolidine-2-carbonitrile,described in WO 00/034241, and commercially available from Novartis),and saxagliptin((1S,3S,5S)-2-[(S)-2-amino-2-(3-hydroxy-adamantan-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carbonitrile,described in WO 01/68603). In addition to these compounds, other DPP IVinhibitors that may be useful in practicing the present invention aredescribed in U.S. Patent Application Publication 2007/0098781 (andpublications referenced therein). DPP-IV inhibitors are typicallyadministered orally.

The agents of the present invention may be prepared in accordance withstandard techniques, disclosed for example in the literature citedherein, including (particularly with respect to the peptide-basedagents) solid-phase synthetic chemistry and recombinant DNA technology(with respect to the amino acid portion of the product), coupled withsubsequent chemical modification, enzymatic modification andcombinations thereof.

The agents may be administered in the form of pharmaceuticallyacceptable salts, e.g., acid-addition salts and basic-addition salts.Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such, asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of such salts includethe sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,mandelate, and the like. Base addition salts include those derived frominorganic bases, such as ammonium or alkali or alkaline earth metalhydroxides, carbonates, bicarbonates, and the like. Such bases useful inpreparing the salts of this invention thus include sodium hydroxide,potassium hydroxide, ammonium hydroxide, potassium carbonate, and thelike. Unless already present in a derivative of the agent, the agentsmay also be administered in the form of a pharmaceutically lower alkylester or amide.

Administration of the agents of the present invention may be via anyroute known to be safe and effective by the physician of ordinary skillin the art. When a therapeutically effective amount of the compositionof the present invention is administered orally, the composition of thepresent invention will be in the form of a tablet, capsule, powder,solution or elixir. When administered in tablet form, the pharmaceuticalcomposition of the invention may additionally contain a solid carriersuch as a gelatin or an adjuvant. When administered in liquid form, aliquid carrier such as water, petroleum, oils of animal or plant originsuch as peanut oil, mineral oil, soybean oil, or sesame oil, orsynthetic oils may be added. The liquid form of the pharmaceuticalcomposition may further contain physiological saline solution, dextroseor other saccharide solution, or glycols such as ethylene glycol,propylene glycol or polyethylene glycol. Controlled release preparationsmay be achieved by the use of polymers to complex or absorb the activecompound used in the present invention. Extended duration may beobtained by selecting appropriate macromolecules, for example,polyesters, polyamino acids, polyvinylpyrrolidone, ethylene/vinylacetate, methylcellulose, carboxymethylcellulose, or protamine sulfate,and by selecting the concentration of macromolecules, as well as themethods of incorporation, in order to prolong release. Such teachingsare known to those of skill in the art and disclosed, e.g., inRemington's Pharmaceutical Sciences, 1980.

In other embodiments, delivery of the active agent is via peripheral,parenteral administration, which as used herein refers to the injectionof a dosage form into the body by a sterile syringe or some othermechanical device such as an infusion pump. Suitable peripheralparenteral routes include intravenous, intramuscular, subcutaneous, andintraperitoneal routes of administration. Formulations suitable forparenteral administration include aqueous and non-aqueous sterileinjection solutions (e.g., a vehicle such as Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection or Lactated Ringer's Injection, which may containanti-oxidants, buffers, bacteriostats and solutes which render theformulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents, preservatives, buffers, antioxidants, orother additives (e.g., wetting or emulsifying agents) known to those ofskill in the art. The formulations may be presented in unit-dose ormulti-dose containers, for example, sealed ampules and vials, and may bestored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid carrier, for example, water forinjections, immediately prior to use. Extemporaneous injection solutionsand suspensions may be prepared from sterile powders, granules andtablets of the kind previously described.

Agents of the present invention may also be administered topically ornasally.

The amount of agents of the present invention will depend upon thenature and severity of the diabetic condition being treated, the natureof prior treatments which the patient has undergone, and on a variety ofother factors, including the type of injury, the age, weight, sex,medical condition of the patient. Ultimately, the attending physicianwill decide the amount of the agent with which to treat each individualpatient. Initially, the attending physician may administer low doses ofagent and observe the patient's response. Larger doses of agent may beadministered until the optimal therapeutic effect is obtained for thepatient, and at that point the dosage is not increased further.

Guidance on methods of determining dosages can be found in standardreferences, for example, Spilker, Guide to Clinical Studies andDeveloping Protocols, Raven Press Books, Ltd., New York, 1984, pp. 7-13and 54-60; Spilker, Guide to Clinical Trials, Raven Press, Ltd., NewYork, 1991, pp. 93-101; Craig et al., Modern Pharmacology, 2d ed.,Little Brown and Co., Boston, 1986, pp. 127-133; Speight, Avery's DrugTreatment Principles and Practices of Clinical Pharmacology andTherapeutics, 3d ed., Williams and Wilkins, Baltimore, 1987, pp. 50-56;Tallarida et al., Principles in General Pharmacology, Springer-Verlag,New York, 1998, pp. 18-20; and Olson, Clinical Pharmacology MadeRidiculously Simple, MedMaster, Inc., Miami, 1993, pp. 1-5.

More specifically, for example, A typical dosage range for GLP-1 andanalogs and derivatives is about 1 pg/kg-1 mg/kg body weight, althoughthese are approximations depending upon a large number of factorsincluding the potency of the analog, its circulating half-life, theindividual characteristics of the subject, and the like. Optimization ofadministration of insulin for diabetic treatment of individuals is wellestablished, and similar optimization protocols are employed here. Forpurposes of illustration, in some embodiments, amounts of native GLP-1range from about 0.03 to about 100 nmol/kg, and GLP-1 is administeredvia injection or by subcutaneous infusion, e.g., at a dose of 4.8pmol/kg/min using a portable pump.

Doses of exendins for achieving enhancement of diabetes resolution willtypically be in the range of about 10 to 30 μg to about 5 mg/day,preferably about 10 to 30 μg to about 2 mg/day and more preferably about10 to 100 μg to about 1 mg/day, most preferably about 30 μg to about 500μg/day, for a 70 kg patient, administered in a single or divided doses.By way of illustration, exendin-4 (commercially available from Amylinand Eli Lilly & Co. under the name BYETTA, and as a generic versionknown as exenatide) is usually administered subcutaneously, in amountsranging from about 5 to about 30 micrograms per day, and in someembodiments, is administered starting with 10 micrograms per day in twodivided doses, and then increased e.g., after about one month, asrequired e.g., to 20 micrograms per day, and even up to about 30micrograms or more per day, for at least e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12 or more additional months. Thus, in some embodiments, theindividual formulation, e.g., for oral administration, contains about 5,10 or 15 micrograms (corresponding to a divided daily total dose of 10,20 or 30 micrograms).

For example, in some embodiments, GIP (1-42) (SEQ ID NO:21) isadministered by subcutaneous infusion in dosages ranging from about 0.1to about 10 pmol/kg/min (e.g., about (1-4 pmol/kg/min) or by bolusinjection ranging from about 6.25 to about 25 nmol/kg/day. By way ofadditional example, in some other embodiments, GIP or GIP analogue isadministered subcutaneously in dosages ranging from about 6.25 to about25 nmol/kg/day, wherein if required, the dosage is increased over thetreatment period or a portion thereof, e.g., with initial dosages ofabout 6.25 nmol/kg/day and a maximum of about 25 nmol/kg/day.

DPP IV inhibitors may be administered at an initial dosage of about 100mg/day. The dosage may be increased if necessary, with a maximum ofabout 200 mg/day.

Individual patients will have varying responses to treatments with thegastrointestinal hormones described herein. Clinicians skilled in theart will therefore appreciate that for some patients a combination ofthe therapies will be more effective than any single therapy alone.Patient clinical and/or biochemical characteristics will guideclinicians in choosing combination therapies to achieve diabetesresolution after gastric restriction surgery. Representativecombinations of hormones suitable for use in the present invention mayinclude GIP and GLP-1; and GLP-1 and the DPP IV inhibitor sitagliptin.

Diabetic resolution is judged to have occurred when evidence of normalglucose metabolism is present. This includes, but is not limited to: afasting glucose below about 125 mg/dL, hbA1c below about 7%, fastinginsulin above about 7 microunits/ml, fasting c-peptide above about 0.4ng/ml, and a 2 hour post glucose loading c-peptide above about 2.0ng/ml. These values may have an uncertainty value of +/−5%.

Once diabetes resolution has occurred, therapy with GLP-1 or analog isdiscontinued. At this point, the patient is encouraged to continue homefasting and glucose monitoring for 30 days. If the fasting glucoseremains below 125, the patient is considered to be non-diabetic. Homeglucose monitoring is then discontinued.

Embodiments of the present invention are now described in connectionwith the following non-limiting examples.

EXAMPLES

The first example is that of a 63 year old, morbidly obese Caucasianmale, with type II diabetes for many years. He weighed 331 pounds andhad a body mass index of 44. His preoperative medications includedrepaglinide and metformin. The patient underwent laproscopic gastricrestriction surgery. He was placed on a low calorie, high protein,bariatric diet and encouraged to exercise regularly. However, heremained diabetic despite experiencing a 56-pound weight loss. He wasstarted on exenatide and instructed to discontinue his prior diabeticmedications. The initial dosage was 10 mcg daily which was advanced to20 mcg after one month.

He lost an additional 44 pounds during the 13 months on exenatide. Thiswas much more than would have been expected by gastric restrictionsurgery alone. His fasting glucose was 95 with post prandial glucosesbelow 150. He was instructed to discontinue exenatide. He continued homefasting glucose monitoring for 30 days. The fasting glucose remainedbelow 125. Home glucose monitoring was then discontinued. He continuedroutine follow care. His diabetes was considered to have been resolved.

The second example is that of a 51-year old, morbidly obese Caucasianmale, with type II diabetes for many years. He weighed 348 pounds andhad a body mass index of 50. His preoperative medications includedmetformin. The patient underwent laparoscopic gastric restrictionsurgery. He was placed on a low calorie, high protein, bariatric dietand encouraged to exercise regularly. However, after 3 months he hadexperienced only a modest weight loss of 15 pounds and remaineddiabetic. He was started on exenatide and instructed to discontinue hisprior diabetic medications. The initial dosage was 10 mcg daily whichwas advanced to 20 mcg after one month.

He lost an additional 51 pounds during the 7 months on exenatide. Thiswas much more than had been expected by gastric restriction surgeryalone. His fasting glucose was 95 with post prandial glucoses below 150.He was instructed to discontinue exenatide. He continued home fastingglucose monitoring for 30 days. The fasting glucose remained below 125.Home glucose monitoring was then discontinued. He continued routinefollow care. His diabetes was considered to have been resolved.

The third example is that of a 71-year old, morbidly obese Caucasianfemale, with type II diabetes for many years. She weighed 315 pounds andhad a body mass index of 55.8. Her preoperative medications includedglimipride, nateglinide and metformin. The patient underwentlaparoscopic gastric restriction surgery. She was placed on a lowcalorie, high protein, bariatric diet and encouraged to exerciseregularly. However, after 3 months she had experienced only a modestweight loss of 21 pounds and remained diabetic. She was started onexenatide. She discontinued her prior diabetic medications after onemonth. The initial dosage of exenatide was 10 mcg daily which wasadvanced to 20 mcg after one month.

She lost an additional 53 pounds during the 7 months on exenatide. Thiswas much more than the amount that would have been expected by gastricrestriction surgery alone. Her fasting glucose and post prandialglucoses were below 110. Her HbA1C was <6%. Her diabetes was consideredto have been resolved.

The fourth example is that of a 55-year old, morbidly obese Caucasianfemale, with recently diagnosed with type II diabetes. She weighed 252pounds and had a body mass index of 40. She was not on preoperativediabetic medications. The patient underwent laparoscopic gastricrestriction surgery. She was placed on a low calorie, high protein,bariatric diet and encouraged to exercise regularly. She was started onexenatide postoperatively. The initial dosage was 10 mcg daily which wasadvanced to 20 mcg after one month.

She lost 96 pounds during the 7 months on exenatide. This was much morethan the amount that would have been expected by gastric restrictionsurgery alone. Her fasting glucose and post prandial glucoses were below110. Her HbA1C was <6%. Her diabetes was considered to have beenresolved.

INDUSTRIAL APPLICABILITY

The present invention has applicability in clinical medicine andtherapeutics, and more specifically for example in the treatment ofobese diabetics.

All patent and non-patent publications cited in this specification areindicative of the level of skill of those skilled in the art to whichthis invention pertains. All these publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A method for increasing diabetes resolution in a diabetic patienthaving undergone gastric restrictive surgery, comprising administeringto the patient an agent that produces an incretin-like effect in thepatient in an amount effective to achieve diabetes resolution whereinthe agent comprises a DPP-IV inhibitor.
 2. The method of claim 1,wherein the DPP-IV inhibitor is sitagliptin.
 3. The method of claim 1,wherein the DPP-IV inhibitor is vildagliptin.
 4. The method of claim 1,wherein the DPP-IV inhibitor is saxagliptin.
 5. The method of claim 1,wherein the amount of the DPP-IV inhibitor is about 100 mg/day.
 6. Themethod of claim 1, wherein the amount of the DPP-IV inhibitor is about300 mg/day.
 7. The method of claim 1, wherein the patient isadministered at least two of said agents.
 8. The method of claim 7,wherein a second agent comprises glucagon-like peptide 1 (GLP-1), or ananalog or derivative of GLP-1.
 9. The method of claim 8, wherein thesecond agent comprises exendin-4.
 10. The method of claim 9, whereinexendin-4 is administered in a daily dosage of about 5 to about 30micrograms.
 11. The method of claim 9, wherein exendin-4 is administeredin a daily dosage of about 10 micrograms.
 12. The method of claim 10,wherein said daily dosage comprises two divided doses.
 13. The method ofclaim 11, wherein said daily dosage comprises about 20 micrograms. 14.The method of claim 9, wherein the patient is administered exendin-4 ina first daily dosage of about 10 micrograms, wherein said first dailydosage is administered for about 1 month, and wherein said patient isthen administered exendin-4 in a second daily dosage of about 20micrograms.
 15. The method of claim 14, wherein said second daily dosageis continued for at least one month.
 16. The method of claim 15, whereinsaid second daily dosage is continued for at least 6 months.
 17. Themethod of claim 15, wherein said second daily dosage is continued for atleast 12 months.
 18. The method of claim 7, wherein a second agentcomprises gastric inhibitory peptide (GIP) or an analog or derivativethereof.
 19. The method of claim 18, wherein the analog of GIP comprisesN-AcGIP (1-42), GIP(1-42) (Lys³⁷PAL), N-AcGIP (1-42)(Lys¹⁶PAL) orN-AcGIP(1-42)(Lys³⁷PAL).
 20. The method of claim 7, wherein a secondagent comprises GIP-1 or an analog or derivative thereof, and GLP-1 oran analog or derivative thereof.
 21. The method of claim 7, wherein asecond agent comprises GLP-1 or an analog or derivative thereof, andsitagliptin.
 22. The method of claim 1, wherein the gastric restrictionsurgery undergone by the patient comprises adjustable gastric binding,vertical banded gastroplasty, gastric stapling, gastric partitioning, orgastric placation.
 23. The method of claim 1, wherein the DPP-IVinhibitor is administered orally.